Sign up to receive free email alerts when patent applications with chosen keywords are publishedSIGN UP

Abstract:

Disclosed are formulations of gamma-hydroxybutyrate in an aqueous medium
that are resistant to microbial growth. Also disclosed are formulations
of gamma-hydroxybutyrate that are also resistant to the conversion into
GBL. Disclosed are methods to treat sleep disorders, including
narcolepsy, with these stable formulations of GHB. The present invention
also provides methods to treat alcohol and opiate withdrawal, reduced
levels of growth hormone, increased intracranial pressure, and physical
pain in a patient.

Claims:

1. A method of rendering an aqueous medium resistant to microbial growth,
comprising adding gamma-hydroxybutyrate salt to the aqueous medium,
adjusting the concentration of the gamma-hydroxybutyrate salt in the
aqueous medium to a final concentration of from about 310 to about 750
mg/ml, and adjusting the pH of the medium to a final pH of about 6 to
about 9, so that the medium is chemically stable and resistant to
microbial growth, wherein the medium does not contain a preservative.

2. The method of claim 1, wherein the salt is sodium
gamma-hydroxybutyrate.

3. The method of claim 1, wherein said pH-adjusting agent is an organic
acid.

5. The method of claim 1, wherein the concentration is from about 450 to
about 600 mg/ml.

6. The method of claim 1, wherein the concentration is about 500 mg/ml.

Description:

RELATED APPLICATIONS

[0001] This patent application is a continuation of U.S. application Ser.
No. 12/913,644, filed on Oct. 27, 2010, which is a continuation of U.S.
application Ser. No. 11/777,877 filed on Jul. 13, 2007 and issued on Dec.
14, 2010 as U.S. Pat. No. 7,851,506, which is a divisional of U.S.
application Ser. No. 10/841,709, filed on May 7, 2004 and issued on Aug.
28, 2007 as U.S. Pat. No. 7,262,219, which is a divisional of U.S.
application Ser. No. 10/194,021, filed Jul. 11, 2002 and issued on Aug.
24, 2004 as U.S. Pat. No. 6,780,889, which is a divisional of U.S.
application Ser. No. 09/470,570, filed Dec. 22, 1999 and issued on Oct.
29, 2002 as U.S. Pat. No. 6,472,431, which claims priority from U.S.
Provisional Patent Application Ser. No. 60/113,745, filed Dec. 23, 1998.
These applications are incorporated herein by reference in their
entirety.

BACKGROUND OF THE INVENTION

[0002] I. Field of the Invention

[0003] The present invention relates generally to the fields of
pharmaceutical compositions to be used in treatments, such as, sleeping
disorders, such as, e.g., narcolepsy (particularly cataplexy), drug
abuse, alcohol and opiate withdrawal, a reduced level of growth hormone,
anxiety, analgesia, effects in certain neurological disorders such as
Parkinson's Disease, depression, certain endocrine disturbances and
tissue protection following hypoxia/anoxia such as in stroke or
myocardial infarction, or for an increased level of intracranial pressure
or the like. The present invention particularly relates to the field of
pharmaceutical production of microbiologically resistant and chemically
stable preparations or solutions of gamma-hydroxybutyrate (GHB), also
known as 4-hydroxybutyrate, and the sodium salt of GHB (sodium oxybate)
and other salts such as magnesium, ammonium and calcium, e.g.

[0004] II. Description of Related Art

[0005] GHB is an endogenous compound with hypnotic properties that is
found in many human body tissues. GHB is present, for example, in the
mammalian brain and other tissues. In brain the highest GHB concentration
is found in the hypothalamus and basal ganglia and GHB is postulated to
function as a neurotransmitter (Snead and Morley, 1981). The
neuropharmacologic effects of GHB include increases in brain
acetylcholine, increases in brain dopamine, inhibition of
GABA-ketoglutarate transaminase and depression of glucose utilization but
not oxygen consumption in the brain. GHB is converted to succinate and
then metabolized via the Krebs cycle. Clinical trials have shown that GHB
increases delta sleep and improves the continuity of sleep (Ladinsky et
al., 1983; Anden and Stock, 1973; Stock et al., 1973; Laborit, 1973;
Lapierre et al., 1988; Lapierre et al., 1990; Yamda et al., 1967;
Grove-White and Kelman, 1971; Scharf, 1985).

[0007] GHB has several clinical applications other than narcolepsy and
sleep disorders. GHB has been reported to reduce alcohol craving, the
number of daily drinks consumed, and the symptoms of alcohol withdrawal
in patients (Gallimberti et al., 1989; Gallimberti et al., 1992; Gessa et
al., 1992). GHB has been used to decrease the symptoms of opiate
withdrawal, including both heroin and methadone withdrawal (Gallimberti
et al., 1994; Gallimberti et al., 1993). It has analgesic effects that
make it suitable as a pain reliever (U.S. Pat. No. 4,393,236).
Intravenous administration of GHB has been reported to reduce
intracranial pressure in patients (Strong, A. 1984). Also, administration
of GHB was reported to increase growth hormone levels in patients (Gerra
et al, 1994; Oyama et al., 1970).

[0008] A good safety profile for GHB consumption, when used long term for
treatment of narcolepsy has been reported. Patients have been safely
treated for many years with GHB without development of tolerance (Scharf,
1985). Clinical laboratory tests carried out periodically on many
patients have not indicated organ or other toxicities (Lammers, 1993;
Scrima, 1990; Scharf, 1985; Mamelack, 1977; Mamelak, 1979; Gallimberti,
1989; Gallimberti, 1992; Gessa, 1992). The side effects of GHB treatment
have been minimal in incidence and degree of severity, though they
include sleepwalking, enuresis, headache, nausea and dizziness (Broughton
and Mamelak, 1979; Mamelak et al., 1981; Mamelak et al., 1977; Scrima et
al., 1989; Scrima et al., 1990; Scharf et al., 1985).

[0009] The pharmacokinetics of GHB have been investigated in alcohol
dependent patients (Ferrara et al., 1992) and in normal healthy males
(Palatini et al., 1993) after oral administration. GHB possesses a rapid
onset and short pharmacological effect (Ferrara et al., 1992; Palatine et
al., 1993; Lee, C., 1977; van der Bogert; Gallimberti, 1989; Gallimberti,
1992; Lettieri and Fung, 1978; Arena and Fung, 1980; Roth and Giarman,
1966; Vickers, 1969; Lee, 1977). In alcohol dependent patients, GHB
absorption into and elimination from the systemic circulation were fast
processes. Virtually no unchanged drug could be recovered in the urine.
There were preliminary indications that the pharmacokinetics of GHB might
be non-linear or dose-dependent (Ferrara et al., 1992). In the healthy
volunteers study, the pharmacokinetics of three rising GHB doses (12.5,
25, and 50 mg/kg) were investigated. These findings indicate that both
the oral absorption and elimination processes of GHB were
capacity-limited though the degree of dose dependency was moderate
(Palatini et al., 1993).

[0010] Organic salts and amides of GHB have been produced to reduce the
physiological side effects of GHB (U.S. Pat. No. 5,380,937). Magnesium
and calcium salt have been produced to reduce the hygroscopic nature of
GHB or powdered forms (U.S. Pat. No. 4,393,236; British Patent No.
922,029). However, problems with the storage of GHB solutions still
exist. GHB degrades into gamma-butyrolactone (GBL) and possibly other
degradants in solution depending upon the pH and other factors. Also, the
contamination by microorganisms in GHB solutions rapidly surpass
acceptable limits, and preservatives can adversely affect the pH and
thus, GHB's stability. As a chronically used product which requires high
levels of drug, the volume of a non-concentrated product creates cost and
handling issues. Thus, there is an immediate need for effective solutions
of GHB that are stable to biological or chemical degradation.

SUMMARY OF THE INVENTION

[0011] The present invention overcomes deficiencies in the prior art by
providing compositions of GHB in an aqueous medium that are resistant to
microbial growth. These compositions are also resistant to the
uncontrolled degradation of GHB into GBL or other substances. The
compositions of the present invention are stable compositions of GHB that
improve shelf-life, and provide a titratable formulation of GHB for easy
dose measurement. In addition, the concentrated solutions embodied in
this invention reduce shipping and storage requirements and allow
patients to carry more drugs for their convenience. The present invention
provides methods to treat a number of conditions treatable by GHB,
referred to herein as "therapeutic categories." Therapeutic categories
for the present invention include, but are not limited to, sleeping
disorders, drug abuse, alcohol and opiate withdrawal, a reduced level of
growth hormone, anxiety, analgesia, effects in certain neurological
disorders, such as Parkinson's Disease, depression, certain endocrine
disturbances and tissue protection following hypoxia/anoxia such as in
stroke or myocardial infarction, or an increased level of intracranial
pressure or other conditions treatable with GHB.

[0012] The invention first provides a pharmaceutical composition of GHB
rendered chemically stable and/or resistant to microbial growth in an
aqueous medium. Preferred GHB salts of the present invention include
sodium, ammonium and calcium. As used herein in certain embodiments,
"stable" may mean resistant to degradation of GHB into its known or
unknown decomposition elements. The level of GBL that is acceptable can
be up to 0.1% of the formulation as per the ICH guidelines for shelf-life
determination. As used herein in certain embodiments, "resistant to
microbial growth" or "resistant to microbial challenge" means that the
formulations meet the criteria set by the Food and Drug Administration
and the U.S. Pharmacopoeia for products made with aqueous bases or
vehicles, which for bacteria means not less than a 1.0 log reduction from
the initial count at 14 days, and no increase from the 14 days count at
28 days, and for yeast and molds, no increase from the initial calculated
count at 14 and 28 days. As used herein in certain embodiments, an
"aqueous medium" may mean a liquid comprising more than about 50% water.
In certain preferred embodiments, an "aqueous medium" may be a solution,
suspension, gel or emulsion of GHB, with a solution of GHB being most
preferred. Preferred gels are thixotropic gels. Compositions that are
resistant to microbial growth are created by dissolving or mixing GHB in
an aqueous medium to a concentration or content of greater than of about
150 mg/ml GHB to the maximal solubility of GHB. The solubility of GHB is
up to about 750 mg/ml at room temperature (20° C. to about
25° C.), however, heating the aqueous medium during preparation up
to 100° C. will increase GHB solubility to at least about 1000
mg/ml. A preferred concentration or content of GHB is about 500 mg/ml.

[0013] The amount of GHB that may be mixed or dissolved into an aqueous
medium and still be resistant to microbial growth depends upon the pH of
the aqueous medium. In certain embodiments the presence of a preservative
may allow the amount of GHB contained in the compositions of the present
invention to be increased and still maintain resistance to chemical
degradation and/or microbial growth. In one embodiment of the present
invention, the pH of the aqueous medium of the pharmaceutical composition
is about 3 to about 10.

[0014] In a preferred embodiment, the pH of said aqueous medium is about 6
to about 7.5. The pH may be from about 3.0 to about 10.3, namely of about
3.0, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6,
about 3.7, about 3.8, about 3.9, about 4.0, about 4.1, about 4.2, about
4.3, about 4.4, about 4.5, about 4.6, about 4.7, about 4.8, about 4.9,
about 5.0, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about
5.6, about 5.7, about 5.8, about 5.9, about 6.0, about 6.1, about 6.2,
about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about
6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5,
about 7.6, about 7.7, about 7.8, about 7.9, about 8.0, about 8.1, about
8.2, about 8.3, about 8.4, about 8.5, about 8.6, about 8.7, about 8.8,
about 8.9, about 9.0, about 9.1, about 9.2, about 9.3, about 9.4, about
9.5, about 9.6, about 9.7, about 9.8, about 9.9, about 10.0, about 10.1,
about 10.2, or about 10.3, and all pH values between each of the listed
pH values, of the aqueous media. This will produce a GHB composition that
is resistant to microbial growth as defined by the test described herein.
As used herein, the term "about" generally means within about 10-20%.

[0015] These pH values will produce compositions resistant to microbial
growth in an aqueous medium if the amount of GHB added, admixed, or
dissolved is from above about 150 mg/ml to about 450 mg/ml, namely, above
about 150 mg/ml, about 160 mg/ml, about 170 mg/ml, about 180 mg/ml, about
190 mg/ml, about 200 mg/ml, about 210 mg/ml, about 220 mg/ml, about 230
mg/ml, about 240 mg/ml, about 250 mg/ml, about 260 mg/ml, about 270
mg/ml, about 280 mg/ml, about 290 mg/ml, about 300 mg/ml, about 310
mg/ml, about 320 mg/ml, about 330 mg/ml, about 340 mg/ml, about 350
mg/ml, about 360 mg/ml, about 370 mg/ml, about 380 mg/ml, about 390
mg/ml, about 400 mg/ml, about 410 mg/ml, about 420 mg/ml, about 430
mg/ml, about 440 mg/ml, to about 450 mg/ml, and all amounts of GHB
between the values listed.

[0016] At the medium to high end of the concentration or content of GHB
that may be dissolved or mixed in the aqueous medium, the maximal pH that
may be used is reduced at room temperature. This is shown in FIG. 1, a
graphical presentation of acceptable formulation ranges. At a
concentration or content of about 450 mg/ml GHB, the pH may be of about
3.9 to about 10.3. At a concentration or content of about 500 mg/ml GHB,
the pH may be of about 4.75 to about 10.3. At a concentration or content
of about 600 mg/ml GHB, the pH may be of about 6.1 to about 10.3. At a
concentration or content of about 750 mg/ml GHB, the pH may be of about
7.0 to about 10.3. Of course, all pH and concentration or content values
in between each of the listed pH and concentration or content values are
encompassed by the invention.

[0017] Certain embodiments may be selected as sub-ranges from these values
of GHB content and aqueous medium pH. For example, a specific embodiment
may be selected as a content of about 170 mg/ml to about 440 mg/ml GHB in
an aqueous medium, at a pH range of about pH 5.5 to about pH 8.7. Another
example of how a range may be selected in an embodiment would be the
selection of a content of about 155 mg/ml of GHB, which is a value
between the above listed values, to a content of about 350 mg/ml of GHB,
and the selection of a pH range of the aqueous medium, such as a pH range
of about 8.87, which is a value between the listed pH values, to a pH of
about 8.93, which is another value between the listed values of pH. A
third example of ranges that may be selected for a specific embodiment
would be selection of a single content or concentration of GHB, such as
about 200 mg/ml of GHB, and the selection of a pH range, such as a pH of
about 3.5 to about 8.2. A fourth example of ranges that may be selected
for a specific embodiment would be selection of a content or
concentration of GHB over a range, such as about 300 mg/ml to about 400
mg/ml, and the selection of a single pH value for the aqueous medium,
such as a pH of about 3. Another example of a range selected for an
embodiment may be the selection of a single content or concentration of
GHB, such as 400 mg/ml GHB, and a single pH value of the aqueous medium,
such as pH 7.7.

[0018] Other examples of how a range of an embodiment of GHB content or
concentration may be selected include a range of GHB content or
concentration from about 200 mg/ml to about 460 mg/ml GHB, encompassing
the ranges for GHB described herein, and a range of pH for the aqueous
medium may be from about pH 4.3 to about pH 7, encompassing ranges for
GHB in an aqueous medium at room temperature described herein. Another
example would be the selection of a range of GHB content or concentration
from about 153 mg/ml to about 750 mg/ml, and a pH range of about 7 to
about 9, encompassing ranges between the listed values of GHB content and
pH described herein. An example may be the selection as a GHB
concentration or content of about 170 mg/ml to about 640 mg/ml in an
aqueous medium, at a pH range of about pH 6.5 to about pH 7.7. Another
example of how a range may be selected in an embodiment would be a
content or concentration of about 185 mg/ml of GHB, which is a value
between the listed values, to a content or concentration of about 750
mg/ml of GHB, at a pH range of about 7.87, which is a value between the
listed pH values, to a pH of about 8.91, which is another value between
the listed values of pH. An additional example of ranges that may be
selected for a specific embodiment would be a content or concentration of
about 200 mg/ml of GHB at a pH of about 7 to about 8.2. Another example
of ranges that may be selected for a specific embodiment would be a
content or concentration of about 750 mg/ml to about 400 mg/ml at a pH of
about 7. Another example of ranges that may be selected for a specific
embodiment would be a content or concentration of about 300 mg/ml to
about 750 mg/ml at a pH of about 8.5 to about 7. Another example of
ranges that may be selected for a specific embodiment would be a content
or concentration of about 400 mg/ml to about 600 mg/ml at a pH of about 9
to about 5.8. And so forth. Thus, all ranges of pH and GHB concentration
or content that can be selected from the values herein and as would be
understood by those of ordinary skill in the art, are encompassed by the
present invention.

[0019] The chemical stability of GHB is affected by pH, with compositions
of GHB in an aqueous medium with a pH below about 6 being less effective
in maintaining the chemical stability of GHB. Compositions with a pH of
greater than about 6.0 are preferred to produce chemically stable
formulations of GHB. Thus, a preferred range to produce chemically stable
GHB would be from about pH 6 to about pH 9. However, all concentrations
or content of GHB in an aqueous medium, as described herein, and as would
be understood by those of ordinary skill in the art, may be selected to
produce compositions of the present invention.

[0020] Additionally, the ranges described above are for a composition at
room temperature, which is defined herein as from about 20° C. to
about 25° C., namely, about 20° C. about 21° C.,
about 22° C., about 23° C., about 24° C., to about
25° C. Within the values and ranges of pH described above, the
ranges of concentration or content of GHB may increase at temperatures
greater than room temperature. Thus, the maximal content or concentration
of GHB in an aqueous medium at a temperature of from about 26° C.
about 100° C., namely about 26° C., about 27° C.,
about 28° C., about 29° C., about 30° C., about
31° C., about 32° C., about 33° C., about 34°
C., about 35° C., about 36° C., about 37° C., about
38° C., about 39° C., about 40° C., about 41°
C., about 42° C., about 43° C., about 44° C., about
45° C., about 46° C., about 47° C., about 48°
C., about 49° C., about 50° C., about 51° C., about
52° C., about 53° C., about 54° C., about 55°
C., about 56° C., about 57° C., about 58° C., about
59° C., about 60° C., about 61° C., about 62°
C., about 63° C., about 64° C., about 65° C., about
66° C., about 67° C., about 68° C., about 69°
C., about 70° C., about 71° C., about 72° C., about
73° C., about 74° C., about 75° C., about 76°
C., about 77° C., about 78° C., about 79° C., about
80° C., about 81° C., about 82° C., about 83°
C., about 84° C., about 85° C., about 86° C., about
87° C., about 88° C., about 89° C., about 90°
C., about 91° C., about 92° C., about 93° C., about
94° C., about 95° C., about 96° C., about 97°
C., about 98° C., about 99° C., to about 100° C. may
be from about 750 to about 1 g/ml, namely to about 751 mg/ml, about 760
mg/ml, about 770 mg/ml, about 780 mg/ml, about 790 mg/ml, about 800
mg/ml, about 810 mg/ml, about 820 mg/ml, about 830 mg/ml, about 840
mg/ml, about 850 mg/ml, about 860 mg/ml, about 870 mg/ml, about 880
mg/ml, about 890 mg/ml, about 900 mg/ml, about 910 mg/ml, about 920
mg/ml, about 930 mg/ml, about 940 mg/ml, about 950 mg/ml, about 960
mg/ml, about 970 mg/ml, about 980 mg/ml, about 990 mg/ml, to about 1000
mg/ml. At temperatures below room temperature, the solubility of GHB may
decrease, and compositions at lower temperature and solubility of GHB at
the pH values and ranges described herein are also encompassed by the
invention. Additionally, differences of atmospheric pressure may also
increase or decrease the solubility of GHB within the ranges described,
and embodiments of the invention with an increased or decreased content
of GHB due to changes in pressure are also encompassed by the invention.
Of course, it is understood that the present invention encompasses
embodiments of GHB concentration or content in an aqueous medium at
higher or lower temperature within the values described herein, such as
about 980 mg/ml to about 200 mg/ml at 95° C. GHB at a pH of about
9 to about 7.5. Or about 150 mg/ml GHB at about 17° C. at about pH
6 to about pH 7. And so forth. Thus, all ranges of pH and GHB content
that can be selected at various temperatures and pressures from the
values above, and as would be understood by those of ordinary skill in
the art, are encompassed by the present invention.

[0021] In certain other embodiments of the present invention, the
pharmaceutical composition may comprise a pH adjusting or buffering
agent. Such agents may be acids, bases, or combinations thereof. In
certain embodiments, the acid may be an organic acid, preferably a
carboxylic acid or alphahydroxy carboxylic acid. In certain other
embodiments, the acid is selected from the group including, but not
limited to, acetic, acetylsalicylic, barbital, barbituric, benzoic,
benzyl penicillin, boric, caffeine, carbonic, citric, dichloroacetic,
ethylenediaminetetra-acetic acid (EDTA), formic, glycerophosphoric,
glycine, lactic, malic, mandelic, monochloroacetic, oxalic,
phenobarbital, phenol, picric, propionic, saccharin, salicylic, sodium
dihydrogen phosphate, succinic, sulfadiazine, sulfamerazine,
sulfapyridine, sulfathiazole, tartaric, trichloroacetic, and the like, or
inorganic acids such as hydrochloric, nitric, phosphoric or sulfuric, and
the like. In a preferred embodiment, the acid is malic or hydrochloric
acid. In certain other embodiments, the pH adjusting agent may be a base
selected from the group including, but not limited to, acetanilide,
ammonia, apomorphine, atropine, benzocaine, caffeine, calcium hydroxide,
cocaine, codeine, ephedrine, morphine, papaverine, physostigmine,
pilocarpine, potassium bicarbonate, potassium hydroxide, procaine,
quinine, reserpine, sodium bicarbonate, sodium dihydrogen phosphate,
sodium citrate, sodium taitrate, sodium carbonate, sodium hydroxide,
theobromine, thiourea or urea. In certain other embodiments, the pH
adjusting agent may be a mixture of more than one acid and/or more than
one base. In other preferred embodiments, a weak acid and its conjugate
base are used to form a buffering agent to help stabilize the
composition's pH.

[0022] In certain embodiments, the composition may contain one or more
salts. A "salt" is understood herein to mean certain embodiments to mean
a compound formed by the interaction of an acid and a base, the hydrogen
atoms of the acid being replaced by the positive ion of the base. Various
salts, including salts of GHB, are also encompassed by ***the invention,
particularly as pH adjusting or buffering agents. Pharmaceutically
acceptable salts, include inorganic acids such as, for example,
hydrochloric or phosphoric acids, or such organic acids as malic, acetic,
oxalic, tartaric, mandelic, and the like. Salts formed can also be
derived from inorganic bases such as, for example, sodium, potassium,
silicates, ammonium, calcium, or ferric hydroxides, and such organic
bases as isopropyamine, trimethylamine, histidine, procaine and the like.
Alkali metal salts such as lithium, potassium, sodium, and the like may
be used, preferably with an acid to form a pH adjusting agent. Other
salts may comprise ammonium, calcium, magnesium and the like. In one
embodiment, a salt of GHB comprising an alkali metal may be combined with
an acid to create a composition that achieves the desired pH when admixed
with an aqueous medium. In another embodiment, a weak base may be
combined with GHB to create a composition that achieves the desired pH
when admixed with an aqueous solution. Of course, other salts can be
formed from compounds disclosed herein, or as would be known to one of
ordinary skill in the art, and all such salts are encompassed by the
invention.

[0023] In certain embodiments, excipients may be added to the invention.
An "excipient" as used herein shall mean certain embodiments which are
more or less inert substances added as diluents or vehicles or to give
form or consistency when the remedy is in a solid form, though they may
be contained in liquid form preparations, e.g. syrups, aromatic powders,
honey, and various elixirs. Excipients may also enhance resistance to
microbial growth, and thus act as a preservative. Such excipients
include, but are not limited to, xylitol, mannitol, lactose, starch,
magnesium stearate, sodium saccharine, cellulose, cellulose derivatives,
magnesium carbonate and the like.

[0025] In certain embodiments, the pharmaceutical composition may also
contain an antioxidant. An "antioxidant" is understood herein to mean
certain embodiments which are substances that inhibits oxidation. Such
antioxidants include, but are not limited to, ascorbyl palmitate,
butylated hydroxyanisole, butylated hydroxytoluene, potassium
metabisulfite, sodium metabisulfite, anoxomer and maleic acid BP.

[0027] Salts, excipients, pH adjusting agents such as acids, bases and
buffering agents, flavoring agents, and other agents that may be combined
with the compositions of the present invention, or may be used to prepare
the compositions of the present invention, are well known in the art,
(see for example, "Remington's Pharmaceutical Sciences" 8th and 15th
Editions, and Nema et al., 1997, incorporated herein in their entirety),
and are encompassed by the invention.

[0028] In certain other embodiments, the pharmaceutical composition
comprises GHB, a pH adjusting or buffering agent, and an aqueous medium,
wherein the components are admixed (sequentially or simultaneously) to
prepare said pharmaceutical composition. The pH adjusting or buffering
agent and aqueous medium may be any described herein.

[0029] The invention also provides a method of preparing a chemically
stable and microbial growth-resistant pharmaceutical composition for the
treatment of a condition responsive to GHB, comprising admixing GHB and a
pH-adjusting or buffering agent in an aqueous medium. In certain
embodiments, the method of preparing the pharmaceutical composition
further comprises admixing a preservative with the pharmaceutical
composition. Other components, such as flavoring agents, salts, and the
like, may be added to the composition. The pH adjusting or buffering
agent, aqueous medium, preservative, flavoring agents, salts, or other
ingredient may be any described herein.

[0030] In certain other embodiments, the method of preparing the
pharmaceutical composition comprises admixing GHB, a pH adjusting or
buffering agent, and an aqueous medium soon before administration to a
patient suspected of having a condition responsive to GHB.

[0031] The invention also provides a method of treating any therapeutic
category of disorder responsive to GHB, comprising administering to a
patient suspected of having such a condition a therapeutic amount of a
pharmaceutical composition comprising chemically stable GHB (e.g. 1-10
gms.) in an aqueous medium resistant to microbial growth. In certain
embodiments, the method of treating a condition responsive to GHB
comprises a patient taking a first dosage of from about 0.1 g to about 10
g, namely about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about
0.6, about 0.7, about 0.8, about 0.9, about 1.0, about 1.1, about 1.2,
about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about
1-9, about 2.0, about 2.1, about 2.2, about 2.3, about 2.4, about 2.5,
about 2.6, about 2.7, about 2.8, about 2.9, about 3.0, about 3.1, about
3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8,
about 3.9, about 4.0, about 4.1, about 4.2, about 4.3, about 4.4, about
4.5, about 4.6, about 4.7, about 4.8, about 4.9, about 5.0, about 5.1,
about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about
5.8, about 5.9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4,
about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about
7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7,
about 7.8, about 7.9, about 8.0, about 8.1, about 8.2, about 8.3, about
8.4, about 8.5, about 8.6, about 8.7, about 8.8, about 8.9, about 9.0
about 9.1, about 9.2, about 9.3, about 9.4, about 9.5, about 9.6, about
9.7, about 9.8, about 9.9, to about 10 grams of GHB, or as needed by the
patient as would be recognized by one of skill in the art. Of course, it
will be understood that all values in between those listed, such as 9.45
grams, 6.32 grams, etc. may be administered, and those values are
encompassed well. In preferred embodiments, the first dose is
administered within an hour of sleep. In preferred embodiments, a second
dose of GHB within the values described above may be administered. This
second dose is administered preferably within about 2.0 to about 5.0 hrs,
namely about 2.0, about 2.1, about 2.2, about 2.3, about 2.4, about 2.5,
about 2.6, about 2.7, about 2.8, about 2.9, about 3.0, about 3.1, about
3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8,
about 3.9, about 4.0, about 4.1, about 4.2, about 4.3, about 4.4, about
4.5, about 4.6, about 4.7, about 4.8, about 4.9, to about 5.0 hours after
the first dose, though it may be administered at a time outside of the
preferred range.

[0032] In certain embodiments, a second pharmaceutical may be administered
with the composition of GHB. Such a second pharmaceutical may be e.g., a
stimulant administered within the same 24 hour period as the first dose
of GHB. The stimulant may be, e.g., but not limited to, methylphenidate
or pemoline to counter the residual effects of GHB treatment during
periods of wakefulness. In certain embodiments, the method of treating a
sleep disorder may include the discontinuation of other second
pharmaceuticals used to control a sleep disorder. Such second
pharmaceuticals may include, but are not limited to, a tricyclic
antidepressant.

[0033] In certain embodiments, the invention provides a method of treating
any appropriate therapeutic category of disorder, by administration of
GHB compositions of the present invention as described above for the
treatment of sleep disorders. When GHB is used in methods of treating any
therapeutic category of disorder, the GHB composition of the present
invention may be mixed with the aqueous medium, and optionally pH
adjusting or buffering agent or other additives, by the patient or
administrator soon before consumption. The patient may prepare the
composition within a few minutes to hours before administration.
Alternatively, one or more of the components may be premixed for ready
use. The components of the GHB composition of the present invention, GHB,
an aqueous medium, pH adjusting or buffering agent, excipients,
preservatives, flavoring agents, and/or other components or additives may
be stored in a container means suitable to aid preservation. Preferably,
the container means is in the form of a set. A "set" as used herein
certain embodiments is one or more components of the composition packaged
in a container or other suitable storage means.

[0034] The present invention also provides a set for the treatment of a
condition responsive to GHB comprising, in suitable storage means, GHB
and a pH adjusting or buffering agent. In certain embodiments, the GHB
and the pH-adjusting or buffering agent are separately packaged. In
certain other embodiments the GHB and the pH adjusting or buffering agent
may be mixed. The set may contain an aqueous medium. In certain other
embodiments, at least one component selected from the group including,
but not limited to, GHB, the pH-adjusting or buffering agent and/or an
aqueous medium is separately packaged. In certain other embodiments, at
least two of the components selected from the group comprising GHB, a pH
adjusting or buffering agent and an aqueous medium are mixed together. In
some embodiments, the set further contains a preservative. Such a set may
have one, two, or more components from the group comprising GHB, a
pH-adjusting or buffering agent, an aqueous medium or a preservative
packaged separately. Such a set may have two or more components mixed
together. Thus, both liquid and dry formulations of GHB and other
components may be packaged in a set for mixing before administration, or
one or more components may be premixed and packaged together with other
components, or all the components may be premixed and packaged in a set.

[0035] It is understood that the compositions of the present invention,
including those in a set, may be dispersed in a pharmaceutically
acceptable carrier solution as described below. Such a solution would be
sterile or aseptic and may include water, co-solvent vehicle buffers,
isotonic agents, pharmaceutical aids or other ingredients known to those
of skill in the art that would cause no allergic or other harmful
reaction when administered to an animal or human subject. Therefore, the
present invention may also be described as a pharmaceutical composition
of GHB with increased stability in a pharmaceutically acceptable carrier
solution.

[0036] Unless defined otherwise, all technical and scientific terms used
herein have the same meaning as commonly understood by one of ordinary
skill in the art to which this invention belongs. Also as used herein,
the term "a" "an" or "the" is understood to include the meaning "one or
more". Although any methods and materials similar or equivalent to those
described herein can be used in the practice or testing of the present
invention, the preferred methods and materials are now described.

BRIEF DESCRIPTION OF THE DRAWINGS

[0037] The following drawings form part of the present specification and
are included to further demonstrate certain aspects of the present
invention. The invention may be better understood by reference to one or
more of these drawings in combination with the detailed description of
specific embodiments presented herein.

[0038] FIG. 1. The Range of Gamma-Hydroxybutyrate's Resistance to
Microbial Growth and Chemical Stability in Aqueous Solution. The ordinate
is the pH of solutions of GHB. The axis is the concentration (mg/ml) of
GHB in aqueous solution. The region below the diagonal line [/] is the
range of GHB solubility at room temperature. Greater solubility can be
achieved, up to 1 g/ml, by heating the solution up to 100° C.

[0039] FIG. 2 illustrates the concentration and volume of GHB solution
that a patient administers (see also Table 4).

DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

I. Formulations of Gamma-Hydroxybutyrate

[0040] A. Microbial Growth and Gamma-Butyrolactone Formation

[0041] The present invention arises from the discovery of chemically
stable and microorganism resistant formulations of GHB in an aqueous
medium, preferably a solution, and the efficacy of these formulations in
the treatment of therapeutic categories of disorders, such as narcolepsy
and other sleep disorders. Specifically, GHB is prepared at a
concentration greater than about 150 mg/ml in an aqueous medium, up to
the limits of GHB's solubility or retention in an aqueous medium, to
produce the compositions of the present invention.

[0042] The maximum solubility of GHB is affected by the pH of the aqueous
medium. At about pH 4, the maximum amount of sodium-GHB that can be
dissolved is about 450 mg/ml. The value of pH that is conducive to GHB
solubility increases, as is shown at FIG. 1, so that the minimal pH that
will dissolve 750 mg/ml GHB was found to be about pH 6.8. This is shown
in Table 1.

[0043] The pH of the aqueous medium also affects the resistance of the
composition to microbial growth at about 500 mg/ml GHB. GHB at this
concentration in an aqueous medium that is between about pH 5 and pH 9 is
resistant to microbial growth, with compositions at about pH 6 to about
pH 7.5 being particularly resistant to microbial growth. However, at
concentrations of GHB greater than about 750 mg/ml above about pH 7.5,
the resistance to microbial growth is reduced. This is shown at Table 2.

[0044] The data from Table 1 and Table 2 are graphically shown in FIG. 1.
The concentration of GHB in the composition, when evaluated in
relationship to the pH, affects the resistance of the GHB composition to
microbial challenge. Compositions of GHB at or below 150 mg/ml are poorly
resistant to microbial challenge from a pH range of about pH 3 to about
pH 9. However, concentrations of GHB of greater than about 150 mg/ml, up
to about 1000 mg/ml of GHB, are believed to be suitably resistant to
microbial contamination at these pH ranges.

[0045] The chemical stability of GHB is affected by pH. Accordingly, the
method for preparing GHB, as described herein, particularly as disclosed
in the specific examples, varies with pH. GBL begins to form if the pH is
about 6 or less. Compositions with a pH of greater than about 6.0 are
preferred to produce chemically stable formulations of 15 GHB. Thus, a
preferred range to produce chemically stable GHB would be from about pH 6
to about pH 9. However, any pH or range of pH values where a clinically
acceptable amount of GBL is produced is also contemplated as being
preferred, and is encompassed by the present invention. The range of GBL
could be regulatorily broadened with availability of sufficient
toxicological data.

[0046] In certain embodiments of the invention, a pH-adjusting agent may
be added to the composition. The choice of a pH adjusting agent may
affect the resistance to microbial challenge and/or the stability of GHB,
as measured by the reduction in assayable GHB. Compositions of GHB, pH
adjusted with malic acid are resistant to both microbial growth and
chemical degradation of GHB, and are preferred. Other pH adjusting or
buffering agents may be selected. Agents that adjust pH that are selected
on this basis will undergo a taste testing study. However, any pH
adjusting agent disclosed herein or as would be known to one of ordinary
skill in the art is contemplated as being useful in the invention. Of
course, any salt, flavoring agent, excipient, or other pharmaceutically
acceptable addition described herein or as would be known to one of
ordinary skill in the art is contemplated as being useful in the
invention.

[0047] Any of the above formulations may be prepared and/or packaged as a
powdered or dry form for mixing with an aqueous medium before oral
administration, or they may be prepared in an aqueous medium and
packaged. After mixing with an aqueous medium, preferably to prepare a
solution, these formulations are resistant to both microbial growth and
chemical conversion of GHB to GBL, thereby increasing the shelf-life of
therapeutic formulations of GHB in an aqueous medium. These
formulations-then provide an easily titratable liquid medium for
measuring the dosage of GHB to be administered to a patient. Additional
embodiments of the composition and methods of preparation are described
below and in the examples.

[0048] B. Pharmaceutical Compositions

[0049] 1. Pharmaceutically Acceptable Carriers

[0050] Aqueous compositions of the present invention comprise an effective
amount of GHB dissolved or dispersed in a pharmaceutically acceptable
carrier and/or an aqueous medium. The phrases "pharmaceutically or
pharmacologically acceptable" refer to molecular entities and
compositions that do not produce an adverse, allergic or other untoward
reaction when administered to an animal, or a human, as appropriate.

[0051] As used herein, "pharmaceutically acceptable carrier" includes any
and all solvents, dispersion media, coatings, antibacterial and
antifungal agents, isotonic and absorption delaying agents and the like.
The use of such media and agents for pharmaceutical active substances is
well known in the art. Insofar as any conventional media or agent is
incompatible with the active ingredient, its use in the therapeutic
compositions is not appropriate. Supplementary compatible active
ingredients can be incorporated into the compositions. For human
administration, preparations should meet sterility, pyrogenicity, general
safety and purity standards as required by the Food and Drug
Administration (FDA).

[0052] The GHB may be lyophilized for more ready formulation into a
desired vehicle where appropriate. The active compounds may be formulated
for parenteral administration, e.g., formulated for injection via
intravenous, intraarterial, intramuscular, sub-cutaneous, intralesional,
intraperitoneal or other parenteral routes. The preparation of an aqueous
composition that contains a GHB agent as an active component or
ingredient will be known to those of skill in the art in light of the
present disclosure. Typically, such compositions can be prepared as
injectables, either as liquid solutions or suspensions. Solid forms
suitable for using to prepare solutions or suspensions upon the addition
of a liquid prior to injection can also be prepared; and the preparations
can also be emulsified.

[0053] The pharmaceutical forms suitable for injectable use include
sterile aqueous solutions or dispersions; formulations including, e.g.,
aqueous propylene glycol; and sterile powders for the extemporaneous
preparation of sterile injectable solutions or dispersions. In all cases
the form must be sterile and must be fluid to the extent that easy
syringability exists. It must be stable under the conditions of
manufacture and storage and must be preserved against the contaminating
action of microorganisms, such as bacteria and fungi.

[0054] Solutions of the active compounds as free acid or pharmacologically
acceptable salts can be prepared in water suitably mixed with
hydroxypropylcellulose and/or a pharmaceutically acceptable surfactant.
Dispersions can also be prepared in glycerol, liquid polyethylene
glycols, and mixtures thereof as well as in oils. Under ordinary
conditions of storage and use, these preparation may best contain a
preservative to further prevent the growth of microorganisms.

[0055] A GHB composition of the present invention can be formulated into a
composition in a neutral or salt form. Such salts can be formed from any
of the acids and bases described herein particularly depending on the
particular GHB or GHB salt used, or as would be known to one of ordinary
skill in the art.

[0056] The carrier can also be a solvent or dispersion medium containing,
for example, water, ethanol, polyol (for example, glycerol, propylene
glycol, and liquid polyethylene glycol, or the like), suitable mixtures
thereof, and vegetable oils. The proper fluidity can be maintained, for
example, by the use of a substance, such as lecithin (e.g. a coating), by
the maintenance of the required particle size in the case of dispersion
and by the use of surfactants. The prevention of the action of
microorganisms can be brought about by any of the preservatives described
herein, or as would be known to one of ordinary skill in the art,
including various antibacterial and antifungal agents, for example,
parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
In many cases, it will be preferable to include isotonic agents, for
example, sugars or sodium chloride. Prolonged absorption of the
injectable compositions can be brought about by the use in the
compositions of agents delaying absorption, for example, aluminum
monostearate.

[0057] Sterile injectable solutions are prepared by incorporating the
active compounds in the required amount in the appropriate solvent with
various of the other ingredients enumerated above, as required, followed
by filtered sterilization. Generally, dispersions are prepared by
incorporating the various sterilized active ingredients into a sterile
vehicle which contains the basic dispersion medium and the required other
ingredients from those enumerated above. In the case of sterile powders
for the preparation of sterile injectable solutions, the preferred
methods of preparation are vacuum-drying and freeze-drying techniques
which yield a powder of the active ingredient plus any additional desired
ingredient from a previously sterile-filtered solution thereof. The
preparation of more, or highly, concentrated solutions for direct
injection is also contemplated, where the use of DMSO as solvent
(although DMSO may not now be a permitted human drug) is envisioned to
result in extremely rapid penetration, delivering high concentrations of
the active agents to a small area.

[0058] Upon formulation, solutions will be administered in a manner
compatible with the dosage formulation and in such amount as is
therapeutically effective. The formulations are easily administered in a
variety of dosage forms, such as the type of injectable solutions
described above, but drug release capsules and the like can also be
employed.

[0059] For parenteral administration in an aqueous solution, for example,
the solution should be suitably buffered if necessary and the liquid
diluent first rendered isotonic with sufficient saline or glucose. These
particular aqueous solutions are especially suitable for intravenous,
intramuscular, subcutaneous and intraperitoneal administration. In this
connection, sterile aqueous media which can be employed will be known to
those of skill in the art in light of the present disclosure. For
example, one dosage could be dissolved in 1 ml of isotonic NaCl solution
and either added to 1000 ml of fluid or injected at the proposed site of
infusion, (see for example, "Remington's Pharmaceutical Sciences"15th
Edition, pages 1035-1038 and 1570-1580). Some variation in dosage will
necessarily occur depending on the condition of the subject being
treated. The person responsible for administration will, in any event,
determine the appropriate dose for the individual subject. The active GHB
may be formulated within a therapeutic mixture to comprise about 100 to
about 10,000 milligrams per dose. Multiple doses can also be
administered.

[0060] In addition to the compounds formulated for parenteral
administration, such as intravenous or intramuscular injection, other
pharmaceutically acceptable forms include, e.g., tablets or other solids;
liposomal formulations; time release capsules; and any other form
currently used, including cremes, which then may be admixed with an
aqueous medium for oral administration.

[0061] One may also use nasal solutions or sprays, aerosols or inhalants
in the present invention. Nasal solutions are usually aqueous solutions
designed to be administered to the nasal passages in drops or sprays.
Nasal solutions are prepared so that they are similar in many respects to
nasal secretions, so that normal ciliary action is maintained. Thus, the
aqueous nasal solutions usually are isotonic and slightly buffered to
maintain a pH of 5.5 to 6.5, though other pH ranges disclosed herein the
specific examples, such as pH 3 to about pH 9, or pH 6 to about 7.5, are
contemplated. In addition, preservatives, similar to those used in
ophthalmic preparations, and appropriate drug stabilizers, if required,
may be included in the formulation. Various commercial nasal preparations
are known and include, for example, antibiotics and antihistamines and
are used for asthma prophylaxis.

[0062] The preferred oral formulations may include such normally employed
excipients, as, for example, pharmaceutical grades of xylitol, mannitol,
lactose, starch, magnesium stearate, sodium saccharin, cellulose,
magnesium carbonate and the like. These compositions can take the form of
solutions, suspensions, tablets, pills, capsules, sustained release
formulations or powders to be admixed with an aqueous medium. In certain
defined embodiments, oral pharmaceutical compositions will comprise an
inert diluent or assimilable edible carrier, or they may be enclosed in
hard or soft shell gelatin capsule, or they may be compressed into
tablets, or the GHB may be packaged separately from or in combination
with the excipients, salts, flavorings or any other components described
herein, to be admixed with an aqueous medium for oral or injectable
formulations, or they may be incorporated directly with the food (i.e. a
beverage) of the diet.

[0063] For oral therapeutic administration, the active compounds may be
incorporated with excipients and used in the form of tablets, buccal
tablets or tabs, troches, capsules, elixirs, suspensions, syrups, wafers,
and the like, to be admixed with an aqueous medium. Such compositions and
preparations should contain at least 0.1% of active compound. The
percentage of the compositions and preparations may, of course, be varied
and may conveniently be between about 2 to about 75% of the weight of the
unit, or preferably between 25-60%. The amount of active compounds in
such therapeutically useful compositions is such that a suitable dosage
will be obtained.

[0064] The tablets, troches, pills, capsules and the like may also contain
the following: a binder, natural as gum tragacanth, acacia, cornstarch,
or gelatin or synthetic as polyvinyl acetate; excipients, such as
dicalcium phosphate; a disintegrating agent, such as corn starch, potato
starch, alginic acid and the like; a lubricant, such as magnesium
stearate; and a sweetening agent, such as sucrose, lactose or saccharin
may be added or a natural or synthetic flavoring agent. When the dosage
unit form is a capsule for admixing with a specific volume of an aqueous
medium, it may contain, in addition to materials of the above type, a
liquid carrier. Various other materials may be present as coatings or to
otherwise modify the physical form of the dosage unit. For instance,
tablets, pills, or capsules may be coated with sugar, natural or
synthetic polymers, or both. A syrup or elixir may contain the active
compounds, sucrose as a sweetening agent, a preservative, a dye and/or a
flavoring.

[0065] Additionally, any excipient, salt, acid, pH-mediating, adjusting or
buffering compound or agent, flavoring, solution, solvent, dispersion,
glycerol, glycol, oil, antibacterial and antifungal agents, antibiotics
and antihistamines, binders, disintegrating agents, lubricants,
sweetening agents, or any other additive or ingredient from those
enumerated above or in the examples, or in any pharmaceutically
acceptable composition or carrier described herein, or as would be known
by one of skill in the art, is contemplated for use in aqueous mediums or
solid forms of the GHB compositions of the invention. One or more of
these compositions may be packaged with GHB or packaged separately from
GHB prior to consumption. If packaged separately, useful compositions of
GHB may be obtained by mixing GHB with the other components with an
aqueous medium prior to consumption. Such components may be packaged in a
set, described below.

[0066] 2. Sets

[0067] Therapeutic sets of the present invention are sets comprising GHB.
Such sets will generally contain, in suitable container, a
pharmaceutically acceptable formulation of GHB. The set may have a single
container, or it may have distinct container for each component, or
distinct container for various combinations of components.

[0068] When the components of the set are provided in one or more liquid
formulations, the liquid formulation is an aqueous medium, with a sterile
aqueous solution being particularly preferred. The GHB compositions may
also be formulated into a syringeable composition. In which case, the
container means may itself be a syringe, pipette, vial, ampule or other
such like apparatus, from which the formulation may be applied to an
infected area of the body, injected into an animal, or even applied to
and mixed with the other components of the set.

[0069] However, the components of the set may be provided as dried
powder(s). When reagents or components are provided as a dry powder, the
powder can be reconstituted by the addition of a suitable solvent. It is
envisioned that the solvent may also be provided in another container
means.

[0070] The container means will generally include at least one vial, test
tube, flask, bottle, pouch syringe or other container means, into which
the GHB formulation or components thereof are placed, preferably,
suitably allocated. The sets may also comprise a second container means
for containing a sterile, pharmaceutically acceptable buffer or other
diluent.

[0071] The sets of the present invention will also typically include a
means for containing the vials in close confinement for commercial sale,
such as, e.g., injection or blow-molded plastic containers into which the
desired vials are retained.

[0072] Irrespective of the number or type of containers, the sets of the
invention may also comprise, or be packaged with, an instrument for
assisting with the injection/administration or placement of the GHB
composition within the body of an animal. Such an instrument may be a
drinking cup, syringe, pipette, or any such medically approved delivery
vehicle.

II. Methods of Treatment with the GHB Compositions

[0073] Because GHB has been shown to be effective in treating narcolepsy
and sleep disorders (Lee, 1977; Mamelak, 1977; Hoes, 1980; Scharf, 1985;
Scrima, 1990; Gallimberti, 1992; Series, 1992; Lammers, 1993), reducing
alcohol craving and alcohol withdrawal symptoms, (Gallimberti et al.,
1989; Gallimberti et al., 1992; Gessa et al., 1992), reducing opiate
withdrawal symptoms (Gallimberti et al, 1994; Gallimberti et al., 1993),
reducing pain (U.S. Pat. No. 4,393,236), reducing intracranial pressure
in patients (Strong, A. 1984), and increasing growth hormone levels in
patients (Gerra et al, 1994; Oyama et al., 1970), the formulations of the
present invention are also contemplated to be useful in the treatment of
any of these disorders or conditions in patients. GHB has also been used
alone as a narcotic in patients with a terminal carcinomatous state. GHB
has been used with other analgesics, neuroleptics, or with a subliminal
barbiturate dose for use as an anesthesia. GHB has been used in closed
cranio-cerebral trauma and as a soporific (U.S. Pat. No. 5,380,937). The
inventors contemplate the use of the GHB compositions of the present
invention as a narcotic, hypnotic, or as a soporific. The inventors also
contemplate the use of the GHB compositions of the present invention in
combination with analgesics, neuroleptics or barbiturates for use as an
anesthesia. The GHB compositions of the present invention may be prepared
and administered by any of the means described herein. particularly those
described in the section "Pharmaceutical Compositions" and the examples,
or by any means as would be known to those of skill in the art.

[0074] The following examples are included to demonstrate preferred
embodiments of the invention. It should be appreciated by those of skill
in the art that the techniques disclosed in the examples which follow
represent techniques discovered by the inventor to function well in the
practice of the invention, and thus can be considered to constitute
preferred modes for its practice. However, those of skill in the art
should, in light of the present disclosure, appreciate that many changes
can be made in the specific embodiments which are disclosed and still
obtain a like or similar result without departing from the spirit and
scope of the invention.

EXAMPLE 1

Preferred Embodiments

Xyrem® Clinical Trials

[0075] The inventors developed a liquid formulation composed of GHB,
xylitol, and preservative in water (XYREM®). Subsequent instability
of the preservative in this formulation and a desire to initiate clinical
trials in a timely manner led to a change in the formulation to a foil
pouch. One clinical trial utilized a twin-pouch dosage form, with one
side (pouch 1) of the foil packet containing GHB and the other side
(pouch 2) containing the flavoring agents (Xylitol, [NF]; Malic Acid, NF.

[0076] Patients were instructed to open the twin-pouch with a scissors,
empty the contents into a dosing cup, add 2 ounces of water, snaphthe lid
on the dosing cup, shake to dissolve, and drink the entire contents of
the cup. Clinical trials conducted by the inventors have been performed
using the twin-pouch dosage form.

[0077] However, the inventors have continued development of a liquid
solution and have now overcome inherent problems with particular
formulations and/or preservatives. The inventors have converted patients
currently enrolled in a GHB open-label trial to a liquid solution
composed of GHB, malic acid, and water--that is diluted with water
immediately prior to oral administration.

[0078] The need for a liquid solution dosage form is further evidenced by
the range of doses being used in a subsequent GHB open-label trial. Three
sizes of pouches were prepared for the GHB open-label trial: 1.5 grams,
3.0 grams. and 4.5 grams. The initial dose for all patients in the GHB
open-label trial was 6 grams of GHB nightly in divided doses. Dosage
adjustments were permitted in the first two weeks of the trial as
indicated for intolerance or lack of efficacy. The investigator was
permitted to decrease the dose of GHB to 3 grams or 4.5 grams, or
increase the dose to 7.5 grams or 9 grams nightly. After two weeks,
further dosage adjustments were made if clinically indicated.

[0079] Thirty-five patients had their dose increased, and 16 patients had
their dose decreased. Patients in the lowest dose group were
disproportionately female and weighed 15 kg less than patients in the
other two groups. Current dosing levels are noted below:

[0080] To achieve these individualized doses, it has been necessary to
provide a combination of different dose strengths. This complexity would
be very difficult to achieve with a marketed product. In addition, a
month's supply of twin-pouches is quite bulky. A liquid formulation
allows for ease in dosing adjustment with one dosage form. In addition
"child-resistant" packaging has been developed with the liquid
formulation.

[0081] A number of patients have also complained about the flavor with the
twin-pouches. As follow-up the inventors sent questionnaires to
participants in the inventors' clinical trial, and performed taste
testing in normal volunteers. The questionnaire responses, taste testing
results, and the clinical experience in narcolepsy patients of the study
administrator have all confirmed that unflavored solutions were
acceptable.

[0082] The concentration and volume of the GHB solution that the patient
administers will be the same irrespective of whether it is dissolved from
the pouch or diluted from the liquid. This is illustrated in FIG. 2 and
Table 4:

TABLE-US-00004
TABLE 4
Comparison of Liquid Solution to Twin-Pouch
Twin-Pouch Liquid Solution
Amount of GHB 3 grams (1 pouch) 3 grams (6 mL)
Inactive Components malic acid malic acid
xylitol
lemon/lime flavor
orange flavor
Final Concentration 50 mg/mL 50 mg/mL*
Final Volume 60 mL 60 mL
*Final concentration outside the range of the most stable formulation.
This formulation strength may be only stable at short periods of time
such as 48 hours. The twin pouch version could be solubilized at a a
concentration within the preferred range of pH and GHB concentration for
longer term storage.
Apart from the elimination of the sweetener (xylitol) and flavoring, the
two formulations result in identical solutions.

Conclusions

[0083] The concentration and volume of the GHB solution that the patient
administers is the same irrespective of whether it is dissolved from the
pouch or diluted from the liquid. Either method may be used to produce
acceptably stable solutions of GHB.

EXAMPLE 2

Preferred Embodiments

Self Preserving Formulations of Gamma-Hydroxybutyrate

Summary of Formulation Studies--Liquid Xyrem®

I. Maximum Solubility Range

[0084] As seen in FIG. 1 and Table 1, the solubility of GHB varies with pH
levels at room temperature (25° C.). Additional amounts of GHB can
be solubilized in a gel if heat is applied, in which case a 1000 mg/ml
concentration can be achieved. The inventors to contemplate that though
the concentrations or contents of GHB shown in FIG. 1 and Table 1 are
preferred for use, due to the ease of preparing and consuming unheated
preparations, higher concentrations of GHB in aqueous medium may also be
made, up to 1000 mg/ml.

II. Microbial Testing

[0085] The inventors used a three factor analysis involving pH,
concentrations of GHB and the pH adjuster used. As seen in FIG. 1, and
Table 2, unacceptably low resistance to microbial challenge was seen at
150 mg/ml GHB at pH 3, 5, 7, and 9.0, using HCl as the pH adjusting
agent. 150 mg/ml GHB at pH 10.3 without a pH adjusting agent also proved
unacceptably resistant to microbial challenge. Borderline acceptable
microbial preservativeness was seen in a solution pH adjusted with HCl at
500 mg/ml GHB at pH 9. At a concentration of 500 mg/ml at pH 6.0 or 7.5,
adjusted with either malic acid or HCl, and 500 mg/ml at pH 9.0 adjusted
with HCl, the formulation is very effective in a microbial challenge
test. The inventors contemplate that a concentration of greater than
about 150 mg/ml of GHB, up to the maximal solubility in aqueous solution
of GHB, will be suitably resistant to microbial challenge from about pH 3
to pH 10.3. Preferably, the aqueous medium will contain a pH-adjusting or
buffering agent.

III. Gamma-Butyrolactone Degradation Range

[0086] GBL begins to form if the pH is about 6 or less with the
formulation tested thus far.

A. Liquid Formulation Development

[0087] The objective of these experiments was to develop a commercial
formulation for sodium gamma hydroxybutyric acid. The initial formulation
for sodium gamma hydroxybutyric acid (GHB) was intended to be an aqueous
liquid formulation containing 150 mg/ml GHB, preservatives and flavoring
agents. To develop this formulation, studies were conducted to establish
the: solubility of the drug in water and as a function of pH, type and
concentrations of suitable preservatives, type and concentrations of
flavor ingredients, and stability of the formulations.

[0088] 1. Solubility

[0089] The feasibility of preparing formulations containing 150 mg/mL of
GHB at pH 3, 5 and 7 was established. Solutions containing 150 mg/mL GHB
were prepared. The initial pH was greater than pH 7.5 and the final pH
was adjusted to 3, 5 or 7 with hydrochloric acid. The solutions were
observed for precipitation and assayed by HPLC for GHB content. The
results showed that no precipitation was observed and the drug
concentration was found to be 150 mg/mL by HPLC. This information was
used as the basis for additional formulation development studies.

[0092] The preservative used in each formulation is marked with an X. The
results showed that formulations #3, 4, 6 and 9 reduced all three
challenge microorganisms by >99.99% in 48 h of contact time.
Formulations #1, 5 and 7 reduced all three challenge microorganism by
>99.99% in 7 days of contact time. Formulations #2, 8, 10, 11, 12 and
13 did not reduce Aspergillus niger mold to >99.99%, although some
reduction occurred in 7 days of contact time. Controls #10, 11, 12 and 13
demonstrated activity against Pseudomonas aeruginosa.

[0093] 3. Stability

[0094] Based on the results of the preservative effectiveness testing,
five formulations were selected for stability testing. Table 6 shows the
composition of the formulations.

[0095] The formulations were packaged in 125 mL, amber PET bottles with
safety lined child-resistant caps and stored upright and inverted at
60° C., 40° C./75% relative humidity (RH) and 25°
C./60% relative humidity. Samples were removed from the stability
chambers after 1, 2 and 3 months and assayed by high performance liquid
chromatography (HPLC) for GHB content. Appearance and pH were also
monitored.

[0096] Table 7 shows the results for the 3 month time point. Samples
stored at 60° C. changed color but samples at all other conditions
remained unchanged in color.

[0097] The pH of all formulations migrated upward over the three month
stability period at 60° C. The percent increase in pH from initial
to 3 months, was greater for the formulations which were initially
adjusted to lower values.

[0098] For example, the migration of pH in formulations 1, 3 and 4
(adjusted down to pH 3) were 21-30 percent across all conditions in three
months. The migration of pH in formulations 2 and 5 (adjusted down to pH
5) were 4.2-12 percent across all conditions in 3 months. Maintenance of
pH becomes important for long term storage since preservatives are known
to degrade in formulations having pH levels above approximately pH 6.

[0099] Additionally, development of flavor systems to mask the negative
taste of preservatives is difficult.

[0101] Based on the above stability data and preservative effectiveness
testing, a pH 5 formulation containing potassium sorbate was selected as
the primary base formulation for flavor system development and
organoleptic testing. A pH 3 formulation containing potassium sarbate was
selected as the back-up formulation.

[0102] B. Dry Powder Formulation Development

[0103] Developing a flavor system for the primary and back-up liquid
formulations proved to be difficult and a decision was made to develop a
dry powder formulation for reconstitution with water before consumption.
This approach removed the need for a preservative system, the requirement
to adjust pH to levels below pH 6, and allowed the development of a
suitable flavor system.

[0104] 1. Dry Powder Formulation Organoleptic Testing

[0105] To develop a flavor system for the powder formulation, several
parameters were evaluated. The flavor attributes of a GHB solution was
characterized by a professional sensory panel. A mimic base containing
similar sensory properties as a GHB solution for flavor system was
developed. Generally Recognized As Safe (GRAS) excipients for flavor
system development were selected. Different excipients (flavorings,
sweeteners, acidulants and flow agents) in the mimic base were screened.
Three flavor systems for the focus group test were selected. A preferred
flavor system was optimized based on comments obtained from the focus
group testing. This final formulation with GHB was optimized.

[0106] Based on the above activities, the following formulations in Table
8 were selected for stability studies:

[0108] A study was initiated to evaluate the stability of the above
prototype formulation in two types of foil packages (high and moderate
moisture resistant) as well as the stability of GHB alone in one type of
foil package (high moisture resistant). Table 9 shows the Lots that were
placed on stability. The foil packages were a high moisture resistant
pouch and a moderate moisture resistant pouch. The study protocol, Table
10, required the samples to be stored at 40±2° C./75±5%
relative humidity for six months, and 25±2° C./60±5%
relative humidity for 12 months. Table 11 shows the tests, methods,
number of packets/test and specifications for the study.

[0109] After two months at 40±2° C./75±5% relative humidity,
the potency (% label claim) of Lots SPO SO ISA and SPO 80 188 was less
than 94.0%, the lower limit of the specification, whereas Lot SPO 8018C
showed no loss in potency. Lots 8018A and 8018B showed approximately 96%
potencies after 2 months at 25° C.±2° C./65%±5%
relative humidity. Lot SPO 8018C again showed no loss in potency at this
lower storage condition.

[0112] Based on the physical changes in state observed during the
stability studies, it was apparent that a solid state interaction between
GHB and the excipient blend had occurred. Since xylitol made up the
majority of the excipient blend, it was assumed that xylitol was the
primary source of the drug-excipient interaction. An alternative
hypothesis was also proposed, based on the possibility that the package
was mediating the interaction between GHB and xylitol. Three studies were
initiated to test these hypotheses.

[0113] 4. Stability of GHB Solids in a Set Container-System

[0114] In the first study, the samples that were stored at 25±2°
C./60±5% relative humidity were transferred to glass vials and then
stored at 40±2° CI7±5% relative humidity. In the second
study, mixtures of GHB and xylitol were gently rubbed between sheets of
different types of foil packaging. The mixtures were observed for changes
in physical appearance. In the third study, different mixtures of GHB and
xylitol were prepared. Differential Scanning calorimetry (DSC)
thermograms were then done to look for changes in the thermograms. The
results of these studies are summarized below.

[0115] Transfer to Glass: Samples of Lot 8018A and Lot 8018C that were
previously stored at 25±2° C./60±5% relative humidity were
transferred to amber screw cap vials and stored at 40±2°
C./75±5% relative humidity. Analyses similar to those shown in Table 6
were done. After 1 month, the potency of Lot 8018A was 94.6% whereas the
potency of Lot 8018C (GHB only) was 100%. In addition, Lot 8018A also
showed evidence of melting. The results supported the hypothesis that GHB
and xylitol were interacting in the solid state and the interaction
appeared to be independent of packaging.

[0116] Foil Study: Mixtures of GHB and xylitol were placed between folded
sheets of several different foil packaging materials. Slight adhesion of
the mixed granules with the foil lining was observed for all of the foils
examined. No direct evidence of melting was observed, however, even when
excessive force was applied to the outer foil surfaces. This data
suggests that the packaging material was not responsible for the solid
state interaction observed during the stability studies.

[0117] DSC thermographs were obtained for samples of GHB/xylitol
containing GHB:xylitol mixtures of 33:66, 45:55 and 55 percent 45
respectively. The scans were conducted at a scan rate of 10°
C./min. The thermograms showed that the sample containing GHB:xylitol
33:66 showed a broad endothermic transition starting at 35°
C.-40° C. Samples with higher ratios of GHB:xylitol also showed
broad endothermic transitions that started at temperatures of 45°
C.-50° C. The changes seen in the thermograms supported the
hypothesis that a solid state interaction may be occurring between GHB
and. xylitol that resulted in low potencies for formulations containing
mixtures of these two agents.

[0118] As a result of the changes seen in the DSC thermograms for
different mixtures of GHB:xylitol, a study was initiated to investigate
the stability of a formulation containing GHB:xylitol excipient blend
55:45. A formulation containing GHB:xylitol excipient blend 33:66 was
used as a control sample. The formulations were packaged in glass vials
and stored at 50° C., 40±2° C./75±5% relative
humidity and 25±2° C./60±5% relative humidity. The
appearance and potency of the formulations were monitored through
analyses of. stability samples. The stability study also showed potency
losses after 1 month at 40° C.±2° C./75±5% relative
humidity with both the 50/50 GHB:xylitol ratio as well as the original
33/66 ratio formulation. Partial evidence of melting was also observed in
both formulations.

[0119] Studies with mixtures of GHB:xylitol excipient blend indicated that
the mixture was incompatible in the solid state. However, when prepared
as an aqueous solution, these mixtures were chemically compatible. Using
this information, a decision was made to package the GHB formulation in
dual pouches; one pouch containing GHB alone and the other containing a
mixture of xylitol and the other flavor ingredients. The formulation wiH
contain equal amounts of GHB and the excipient blend. This product will
be prepared, packaged, and may be checked for stability.

EXAMPLE 3

The Pharmacokinetics of Gamma-Hydroxybutyrate

I. Study Objectives

[0120] The objective of this study was to assess the pharmacokinetics of
GHB after oral administration of two consecutive single doses of GHB (3
g/dose; patients generally ingested the first dose of this medication
prior to bedtime and the second dose from 2.5 to 4.0 h later) to
narcoleptic patients who are maintained on a chronic regimen of GHB.

II. Study Design

[0121] This pharmacokinetic study was conducted as an open-label,
single-center investigation in 6 narcoleptic patients. The study design
is summarized as follows:

[0122] Narcoleptic patients, 18 years of age or older, who volunteered for
this study were screened at least one day prior to the treatment phase.
Each patient was determined to be in stable health and evaluated for the
presence of narcolepsy, defined for the purposes of this example as one
or more years of medical history of narcolepsy as evidenced by a recent
nocturnal polysomnogram (PSG) and a valid score from a Muhiple Sleep
Latency Test (MSLT).

[0123] Patients maintained on GHB were allowed to participate. These
patients had been weaned from antidepressants, hypnotics, sedatives,
antihistamines, clonidine, and anticonvulsants though a stable regimen of
methylphenidate (immediate release or sustained release) was allowed.
Each patient passed a pre-study physical examination (which included
hematology, blood chemistry, urinalysis, and vital signs measurements)
prior to the commencement of the treatment phase.

[0124] Before oral administration of the first GHB dose, an indwelling
catheter was placed in an arm vein and a baseline blood sample was
collected. Each patient then ingested a 3 g dose of GHB before bedtime.
Another 3 g GHB dose was administered 4 h after the first dose.
Twenty-one sequential blood samples were collected over 12 h (starting at
10 min after the first dose and ending at 8 h after the second dose).
Upon completion of the treatment phase, a follow-up physical examination
which included the measurement of vital signs was performed on each
patient within 48 h after the last blood sample. A detailed description
of the trial methodology is presented in Section IV.

III. Inclusion Criteria

[0125] Patients were included in the study if they: had signed an informed
consent prior to beginning protocol required procedures; had not
participated in such a study at an earlier date; were willing and able to
complete the entire study as described in the protocol; were 18 years of
age or older at study entry; had not taken any investigational therapy
other than GHB within the 30-day period prior to screening for this
study; had an established diagnosis of narcolepsy for at least one year
with documentation from a qualified laboratory by a nocturnal
polysomnogram (PSG) and a Multiple Sleep Latency Test (MSLT) which
demonstrated mean sleep latency to be less than 5 min and REM onset in at
least 2 of 5 naps; had not been diagnosed with uncontrolled sleep apnea
syndrome, defined as a sleep Apnea Index of 5 or an Apnea Hypopnea Index
(AHI) greater than 10 per hour or any other cause of daytime sleepiness;
and were free of any medication for their narcolepsy (including
hypnotics, sedatives, antidepressants, antihistamines, clonidine, and
anticonvulsants) other than GHB and methylphenidate (IR or SR). Patients
admitted to this study if they were not experiencing unstable
cardiovascular, endocrine, gastrointestinal, hematologic, hepatic,
immunologic, metabolic, neurological, pulmonary, and/or renal disease
which would place them at risk during the study or compromise the
protocol objective; did not have neurological or psychiatric disorders
(including transient ischemic attacks, epilepsy, or multiple sclerosis)
which, in the investigator's opinion, would preclude the patients'
participation and completion of this study; did not have a current or
recent (within one year) history of alcohol or drug abuse; did not have a
serum creatinine greater than 2.0 mg/dL, abnormal liver function tests
(SGOT or SGPT more than twice the upper limit of normal or serum
bilirubin more than 1.5 times normal). Female patients were entered into
the study if they were either post-menopausal (i.e. no menstrual period
for a minimum of 6 months), surgically sterilized or provided evidence of
effective birth control. Females of childbearing potential must agree to
continue to use an IUD, diaphragm, or take their oral contraceptives for
the duration of the study. Female patients of childbearing potential must
have a negative pregnancy lest upon entry into the study.

IV. Trial Methodology

[0126] A time and events schedule is presented in Table 12.

[0127] A. Screening Period/Washout

[0128] Six narcoleptic patients who were chronically being treated with
GHB were recruited to participate in this pharmacokinetic study. The
screening period was at least one day prior to the treatment phase.
During the screening period each patient completed the following
procedures for the assessment of their physical condition: medical
history evaluation; physical examination evaluation; clinical laboratory
evaluation; inclusion criteria review. Each patient's GHB and
methylphenidate regimen also were recorded on an appropriate case report
form (CRF). The investigator also ensured that there was at least an
8-hour washout period for GHB prior to the treatment.

[0129] B. Treatment Period/Blood Samples Collection

[0130] All patients were hospitalized from approximately four hours prior
to first GHB dosing (around 6 p.m.) until the end of the treatment period
(around 10 a.m. the next morning). Patients ate their dinner at the
clinical research unit soon after arrival and fasted until breakfast next
morning. At least three hours elapsed between the completion of dinner
and the administration of the first GHB dose. An indwelling catheter was
placed in an arm vein of each patient for blood sampling at approximately
30 min and 1 h before the first GHB dose and a baseline blood sample (5
mL) was collected.

[0131] The first GHB dose (3 g) was administered at around 10 p.m. Dosing
of individual patients were staggered. The second GHB dose was
administered at 4 h after the first GHB dose (i.e. immediately after the
4 h blood sample). The exact dosing times in each patient were recorded
on appropriate CRF pages. Blood samples (5 mL each) were collected
through the indwelling catheter into heparinized tubes at 0.2, 0.4, 0.6,
0.8, 1, 1.5, 2, 3, 4, 4.2, 4.4, 4.6, 4, 8, 5, 5.5, 5, 7, 8, 10, and 12 h
after the first GHB dose. Blood samples were processed according to the
procedures described herein. Patients were monitored for adverse
experiences throughout the study according to the specific procedures.

[0132] C. Follow-Up

[0133] Follow-up occurred within 48 h after the last blood sample had been
collected. An abbreviated physical examination which included vital signs
measurement was performed. Adverse experiences and concomitant medication
use, if any, were assessed. Any ongoing adverse experiences and
clinically important findings in a patient were followed to the
investigator's and/or sponsor's satisfaction before the patient was
discharged from the study.

[0134] D. Methods of Assessment

[0135] 1. Medical History

[0136] The medical history was recorded during the screening period. The
history included gender, age, race, height, prior reaction to drugs, use
of alcohol and tobacco, history and treatment, if any, of cardiovascular
pulmonary, gastrointestinal, hepatic, renal, immunologic, neurological,
or psychiatric diseases and confirmation of inclusion criteria.

[0137] 2. Physical Examination

[0138] Physical Examination included body system review as well as
measurement of body weight and vital signs and a neurological
examination.

[0142] All clinical laboratory tests were performed at a local laboratory.
The laboratory tests and analysis were required of each patient included:
hematology, including hemoglobin, hematocrit, red blood cell count, white
blood cell count and differential; fasting blood chemistries included
blood urea nitrogen (BUN), uric acid, glucose, creatinine, calcium,
phosphorus, total protein, albumin, sodium. potassium, SCOT (AST), SGPT
(ALT), alkaline phosphatase, lactate dehydrogenase (LDH), and total
bilirubin; midstream catch urinalysis included specific gravity, pH,
protein, occult blood, ketones and glucose by dipstick determination as
well as a microscopic examination of urine sediment for RBC, WBC,
epithelial cells or casts or crystals; and a urine pregnancy test. if
applicable. Any laboratory parameter that was out of range and considered
clinically significant excluded the patient from participation in this
study. The investigator would provide an explanation of all observations
that were significantly outside the reference range.

[0143] 5. Concomitant Medication

[0144] The continued use of a fixed dose of methylphenidate immediate
release or sustained release (IR or SR) is acceptable. The
methylphenidate regimen was recorded on the appropriate case report form.

[0145] 6. Adverse Experiences

[0146] An adverse experience are any undesirable event experienced by a
patient or volunteer whether or not considered drug-related by the
investigator. An undesirable event can be, but is not limited to,
subjective symptoms experienced by a patient or, objective findings such
as significant clinical laboratory abnormalities. Adverse experience is
considered synonymous with the term "adverse event".

[0147] The investigators report in detail all adverse experiences and
symptoms that occurred during or following the course of trial drug
administration for up to 2 days. Included in the description was the
nature of the sign or symptom; the date of onset; date or resolution
(duration); the severity; the relationship to trial treatment or other
therapy; the action taken, if any; and the outcome.

[0148] A serious adverse experience is defined as one that is fatal, life
threatening, permanently disabling, or which results in or prolongs
hospitalization. In addition, overdose, congenital anomaly and
occurrences of malignancy are always considered to be serious adverse
experiences. An unexpected adverse experience is one not previously
reported.

[0149] Any serious or unexpected adverse experience (including death) due
to any cause which occurs during the course of this investigation,
whether or not it is related to the investigational drug, was reported
within 24 h by telephone or facsimile. Appropriate authorities were to be
informed if the serious or unexpected adverse experience, in the opinion
of inventors, was likely to affect the safety of other patients or
volunteers or the conduct of the trial.

[0152] Labeling: The clinical supplies for individual patients were
packaged in separate containers. Each container included two unit doses,
i.e. two twin-pouches. Clinical supplies for eight patients (including
those for two replacement patients) were delivered to the investigator.
Foil twin-pouches were identified with a two-part label.

[0153] Dose Administration: The investigator or designee prepared the oral
solution for dosing within 30 min prior to the first oral administration
to individual patients. The contents of one twin-pouch was emptied into a
dosing cup to which, two ounces of water were added. After replacing the
lid of the dosing cup, it was gently shaken to dissolve the GHB and
excipient in water. The GHB solution was ingested in its entirety.
Likewise, the second GHB dosing solution was prepared in the same manner
and was ingesting in its entirety at 4 h after the first GHB dose.

[0154] Investigational Drug Accountability: At the conclusion of the
study, all clinical supplies were accounted for on the drug
accountability form and unused drug supplies were returned for proper
disposition.

[0155] 8. Determination of Plasma GHB Concentrations

[0156] Plasma samples were analyzed for GHB by the Department of
Bioanalytical Chemistry (Covance (previously known as Hazelton Coming),
Madison, Wis.) A gas chromatographic method with mass selective detection
(GC-MSD) was used in the analysis.

[0157] 9. Data Management and Analysis

[0158] Data Base: An EXCEL data base (spreadsheet) was constructed from
data recorded on Case Report Forms (CRF) and plasma GHB concentration
data sets received from Covance (Corning Hazleton). Each entry in the
EXCEL spreadsheet was checked against the CRFs and any data entry error
found was corrected.

[0159] Pharmacokinetic Analysis: Pharmacokinetic parameters were
determined for individual sets of plasma GHB concentration vs. time data
using the non-compartmental routine in WinNonlin Version 1.1. The peak
GHB concentrations (Cmax) and the times of their respectively
occurrences (tmax) were observed values. Terminal half-life
(T1/2) was obtained by log-linear regression analysis of the
terminal phase of concentration vs. time curves. The area under the curve
(AUCinf) and the area under the first moment curve (AUMCinf)
were calculated by the linear trapezoidal rule up to the last determined
concentration and included extrapolated areas to time infinity. Apparent
oral clearance (CL/F) was calculated as Dose/AUCinf. Volume of
distribution (Vz/F) was determined by taking the ratio between CL/F
and λz (elimination rate constant). Mean residence time (MRT)
was estimated from the ratio between AUMCinf and AUCinf.

[0160] Safety Analyses: Results of physical examinations, vital signs,
clinical laboratory data were summarized in tabular form and presented by
patient number. Adverse events also were tabulated in a similar fashion.

[0161] 10. Results

[0162] Patient and Study Accountability: Six narcoleptic patients were
enrolled and all six completed the study in its entirety.

[0163] Protocol Compliance: There were no inclusion criteria violations.
All patients admitted into the study met the study entrance requirements
and completed the screening phase at least one day before the treatment
phase.

[0164] All six patients took non-study medications in addition to
methylphenidate and GHB doses because none of their concomitant
medications (Synthroid, Premarin, Lovastatin, Fluvastatin, furosemide,
potassium, hydrochlorothiazide, lansoprazole, and verapamil) were on the
exclusion list (which included hypnotics, sedatives, antidepressants,
antihistamines, clonidine, and anticonvulsants). Adverse experience
probes, vital sign measurements, and essentially all pharmacokinetic
blood samples were performed at protocol specified times; the few
deviations in blood sampling times should not have any impact on the
outcome of the study since actual blood sampling times were used in the
pharmacokinetic analysis.

[0165] The diagnosis of narcolepsy for at least one year in each patient
was verified by a nocturnal polysomnogram (NSG) and a Multiple Sleep
Latency Test (MSLT) conducted at a qualified laboratory. Five patients
have been maintained on GHB nightly for over 10 years and one patient has
been receiving GHB nightly for two years. One patient (Subject 101) also
had multiple sclerosis; however, the attending physician, judged that it
would not interfere with the objective of this study. A few of the
screening clinical laboratory results marginally fell outside the
reference range but none was considered by the attending physician to be
clinically significant.

[0166] Exposure to Study Drug: All patients ingested the two GHB doses as
scheduled (immediately prior to bedtime). The GHB doses per kg body
weight ranged from 26.4 to 52.4 mg/kg.

[0167] Plasma GHB Concentration Profiles: It was noted that, in certain
cases, (Patients #103, and #106), plasma GHB concentrations did not
decline from the first Cmax to zero concentration at h 4. Upon
achievement of the second Cmax the semi-logarithmic plots of
concentration versus time data in Patients #102, #103, and #105 exhibited
a convex decline profile. Such a decline pattern suggested non-linear
pharmacokinetics. The highest plasma GHB concentration observed in the
study was 125.0 μg/mL which occurred in Subject 101 after the second 3
g GHB dose.

[0168] Pharmacokinetic Parameter Estimates: The mean (±SD) showed that
maximum GHB concentrations (Cmax) were 62.8±27.4 μg/mL and
91.2±25.6 μg/mL for the first and second GHB doses, respectively.
The corresponding mean observed times to maximum concentrations were
40±6 and 36±7 min after the first and second GHB doses,
respectively. The mean AUCinf was 17732±4603 μg/mLh. The mean
CL/F was 4.2±mL/min/kg and the mean VZ/F was 307±96 mL/kg. The
mean MRTinf was 249±56 min. The mean GHB T1/2, estimated by
linear regression of log [C] vs. time data of the terminal phase of the
second GHB dose was 53±19 min.

[0169] Adverse Experiences: No adverse experiences were reported in the
study.

[0170] Follow-up Safety Assessments: Inspection of screen and follow-up
physical examination results per individual patient did not identify any
changes attributable to GHB.

[0171] 11. Discussion

[0172] To the inventors' knowledge, the level of GHB in human systemic
circulation has not been reported in the literature. Hence, baseline (0
h) plasma samples were analyzed for GHB concentrations. The GC-MSD method
used in the present study had a limit of quantification (LOQ) of 7.02
μg/mL and analysis of the baseline plasma samples showed the
endogenous levels of GHB are below this sensitivity limit. This finding
was confirmed by adding known amounts of GHB (5, 10, and 25 μg per mL
of plasma) to blank human plasma samples and subjected these samples to
GC-MSD analysis. This method of standard addition allowed an estimation
of the endogenous GHB level in human plasma which was found to average
about 2.02 μg/mL, (i.e. approximately 2/7 of the Limit Of Quantitation
(LOQ) for a validated assay. Hence, the endogenous GHB level was not
subtracted from exogenous GHB concentrations prior to pharmacokinetic
analysis.

[0173] Values of mean tmax (˜40 min after dosing) and t1/2
(˜35 min) suggest that the GHB solution administered to narcoleptic
patients in this study was readily absorbed and rapidly eliminated. In 3
out of 6 patients the drug was essentially gone from the systemic
circulation by h 4 after the first GHB dose whereas in the remaining
three patients residual GHB levels of ˜15 μg/mL was still
detected at h 4.

[0174] The convex nature of the decline of plasma GHB concentrations in
three patients after achievement of the second cmax indicated that
elimination of GHB from the systemic circulation in these three patients
is capacity limited. Nevertheless, it should be noted that plasma GHB
concentrations were no longer detectable by h 6 after the second GHB dose
(10 h after the first GHB dose). The mean apparent oral clearance found
in this study was 4.2±1.0 mL/min/kg and appeared to be comparable to
the apparent oral clearance of 5.3±2.2 mL/min/kg reported in the
literature for a group of alcohol dependent patients who were
administered a dose of 50 mg/kg (Ferrara, 1992). While it appeared that
the GHB dose (ranging from 26.4 to 52.4 mg/kg with a mean of 36.5 mg/kg)
in the present study was lower than the comparison GHB dose (50 mg/kg)
administered to the alcohol dependent patients (Ferrara, 1992), it should
be noted that each patient in the present study was administered two
consecutive GHB doses at four-hour interval and residual GHB levels were
detected in three out of six patients immediately prior to the second GHB
dose. The GHB pharmacokinetic non-linearity in alcohol dependent patients
easily can be observed from the apparent oral clearance which increased
to 8.1±4.8 mL/min/kg when the GHB dose is reduced to 25 mg/kg dose
(Ferrara, 1992). In the present study, the non-linearity was less obvious
because each narcoleptic patient received two consecutive fixed 3 g doses
regardless of body weight.

[0175] The mean elimination half-life of GHB in the six narcoleptic
patients was determined to be 53±19 min, longer than that in alcohol
dependent patients after a 50 mg/kg GHB dose (Ferrara, 1992). The
lengthening of GHB elimination half-life observed in this study partially
was caused by the wider spacing in sampling time points. However,
capacity limited elimination of this drug in some of the narcoleptic
patients also could have contributed to this prolongation.

[0176] GHB appears to have a shortcoming in that its elimination from the
body is capacity limited in some patients when the drug is administered
at a fixed regimen of 3 g twice nightly at four-hour interval. However,
from a therapeutic perspective, GHB offers an advantage in the treatment
of narcolepsy because by the time a patient wakes tip in the morning
(i.e. 8 to 10 h after the fltst GHB dose), all GHB, including that from
the second dose, will have been eliminated from the systemic circulation.
GHB was also well tolerated by narcoleptic patients in this study. No
adverse experience was reported.

[0177] 12. Conclusions

[0178] The capacity limited elimination kinetics was observed in three out
of six patients who had been administered two consecutive 3 g oral doses
of GHB, 4 h apart. From a pharmacokinetic perspective, dividing the
nightly GHB dose into two portions and administering the two portions to
narcoleptic patients at a 2.5- to 4-h interval was rational because the
elimination half-life of GHB was short (<1 h). The pharmacokinetic
profiles of GHB in narcoleptic patients who had been receiving this agent
nightly for years appeared to be comparable to those in alcohol dependent
patients (Ferrara, 1992).

EXAMPLE 4

Sodium Oxybate Formulation Study

I. Study Objectives

[0179] This example described ways that sodium oxybate may be prepared and
tested for stability to determine preferred formulations. Various
formulations of sodium oxybate in water were prepared under different
conditions of mixing and with addition of selected acidulents at multiple
pH levels (Neo-Pharm Laboratories, Blainville, Quebec). Selected
formulations were placed on real time and accelerated stability. Earlier
studies have demonstrated that degradation products are formed in acidic
conditions and that antimicrobial effectiveness is limited at high pH.
Therefore several acidulents across a range of 6.0-9.0 were evaluated.

II. Study Design-Part I

[0180] The following experimental work is designed to be performed in two
stages. Initial studies were conducted to evaluate the impact of
conditions of formulation, pH and acidulent on the resultant levels of
impurities, specified and unspecified, and potency of sodium oxybate.
Sodium oxybate was prepared (MDS Neo-Pharm Laboratories, Quebec Canada),
under different conditions of mixing and with addition of selected
acidulents at multiple pH levels. These formulations of sodium oxybate
acidulent were then tested.

[0181] A. Preliminary Studies

1. Formulations Description

[0182] All formulations were prepared at a concentration of 500 mg/cc of
sodium oxybate in water. Three acidulents (HCl, malic acid, and
phosphoric acid), were selected and tested at pH 6.0, 7.5 and 9.0.

2. Method of Formulation

[0183] Solutions, were prepared using the described methods:

[0184] a. Rapid Mix Method:

[0185] Sodium oxybate was dissolved in water and concentrated acidulent
was added immediately, without temperature control. Temperature of
solution was monitored and recorded prior to and during addition of
acidulent. The time of equilibration to room temperature was also
recorded. After the solution reached ambient room temperature, it was
filtered through a 10 μm filter.

[0186] b. Cool Mix Method:

[0187] Sodium oxybate was dissolved in water. Acidulent was diluted to 10%
and slowly added. The solution was cooled by water with jacket or ice
bath. Monitor and record the temperature of the solution was monitored
and recorded during addition of acidulent. The time of equilibrium from
room temperature was also recorded. The preferred maximum temperature
should be maintained at less than 40° C. The solution was filtered
through a 10 μm filter.

[0188] c. Reverse Order of Addition:

[0189] Acidulent was added to water and cooled to room temperature. The
sodium oxybate was dissolved in the diluted acidulent solution. The
temperature of solution was monitored and recorded during addition of
sodium oxybate. The solution was filtered through a 10 μm filter.

[0190] d. Sodium Oxybate Control:

[0191] Sodium oxybate was dissolved in water to a concentration of 500
mg/cc with no added acidulent. The final pH was recorded and the solution
was filtered through a 10 μm (micron or micrometer) filter.

3. Solution Data:

[0192] Data was recorded for each solution which included: 1) date of
preparation 2) date of analysis, 3) amount of acidulent required to
achieve target pH, 4) length of time for dissolution of sodium oxybate,
5) temperature profile of solution over time of solution preparation to
be recorded at 15 minute intervals, 6) final pH of solution.

4. Testing Requirements:

[0193] The following methods were used to test the prepared solutions: pH,
HPLC (High Pressure Liquid Chromatography) for potency (sodium oxybate),
and for impurities. Time 0 analysis was performed immediately (within 24
h). RRT=(relative retention time).

[0194] B. Summary of Part I:

[0195] 1. Preliminary Evaluation of Sodium Oxybate Formulations

[0196] Tables 13, 14 and 15 provide test results for the three methods of
preparation of sodium oxybate formulations.

[0198] Review of the data indicated that the optimum method for
preparation of sodium oxybate with minimal impurity levels is Method B:
Controlled mixing with diluted acidulent. Method 2b resulted in
formulations with lowest levels of GBL.

[0199] 2. Conclusions.

[0200] Additional evaluations were carried out on selected formulations:
1) sodium oxybate with HCl as acidulent, at pH 7.5, and 2) sodium oxybate
with malic acid as acidulent, pH 6.0, 7.5, and 9.0.

III. Study Design-Part II

[0201] Microbial Challenge and Stability Tested to determine the most
preferred embodiments, the number of formulations was limited to three
based on the data prepared from the above experiments.

[0202] A. Kinetic Stability Study with Selected Formulations

[0203] Samples of formulations are stored in tightly closed containers.
Storage Conditions were 25° C., 40° C., and 60° C.
Time points in brackets were tested at the inventor's discretion. The
samples were tested according to the following schedule: at 25° C.
storage temperature, the assay points will be 0, 14, 28, 45, 60 days and
120 days; at 40° C. storage temperature, the assay points will be
0, 7, 14, 28, 45, 60 days; at 60° C. storage temperature, the
assay points will be at 0, 3, 7, 14, 28, 45 days, and, 60 days.

[0204] The testing requirements included pH, HPLC for sodium oxybate
(duplicate injections of single sample preparation), and impurities,
specified and unspecified.

[0205] B. Preservative Effectiveness Testing of Selected Formulations

[0206] Microbial challenge testing of formulations was preformed according
to USP XXIII, <51>, Eighth Supplement. Solutions are determined to
"Pass or Fail" based upon the USP criteria for preservative effectiveness
which states: For Bacteria, "Not less than 1 log reduction from the
initial microbial count at 14 days and no increase from the 14 days count
at 28 days;" and for yeast and molds, "No increase from the initial
calculated count at 14 and 28 days." Solutions which met these criteria
were designated as "Pass" and those that did not meet these criteria were
designated as "Fail".

[0207] C. Summary Stability Results:

[0208] 1. Formulations Prepared with Malic Acid as Acidulents: [0209] a.
Malic Acid, pH 6.0 formulation (25°), GBL and impurity A levels
were very low an Day 0, however, by Day 45 GBL levels had reached 2.8%.
Impurity A increased from 0.01 to 1.0%, and pH increased from 6.0 to 6.3
by day 45. This formulation stored at 40° C. and 60° C.
showed GBL levels up to 5.4%, impurity A levels increased to 2.3%, and pH
increased to 6.3 by Day 14. [0210] b. Malic Acid, pH 7.5 formulation
(25° C.), GBL levels were 0.009% on Day 0, and increased to 0.17%
by day 45. Impurity A increased from 0.01% to 0.1% and pH increased from
7.5 to 7.9. Malic acid, pH 7.5 GBL levels are reached (40° C.) and
60° C. a maximum of 0.22%. Impurity A levels reached 0.1% and pH
increased to 8.0. Under accelerated conditions, all parameters reached an
apparent maximum by Day 7 and did not increase significantly thereafter.
[0211] c. Malic Acid, pH 9.0 formulation (25° C.) GBL levels
measure 0.008% on Day 0, and increased slightly to 0.013% on Day 45.
Impurity A did not increase nor did pH increase. Under accelerated
conditions, GBL increased from 0.008% to a maximum of 0.018% by Day 14.
Impurity A increased slightly from 0.10 to 0.014% by Day 14.

[0214] HCl, pH 7.5 formulation (25%) GBL levels measured 0.041% on Day 0,
Impurity A measured 0.02%, and by Day 18 GBL measured to 0.12% and
impurity A to 0.07%. Under accelerated conditions (40° C. and
60° C.), GBL increased to a maximum of 0.21%, impurity A increased
from 0.02% to 0.1%, and pH increased from 7.5 to 8.0. As with Malic Acid
at pH 7.5, the measured parameters reached maximum by Day 7 and did not
increase significantly thereafter.

[0217] Formulations selected for microbial challenge testing were the
following: HCl, Ph 7.5, and malic acid, Ph 7.5. The rationale for this
decision was twofold. First, the formulations were selected based on
minimal formation of GBL and impurity A. Second, the formulations were
selected to maintain a Ph in the neutral range.

EXAMPLE 5

Further Evaluation of Sodium Oxybate Formulations

[0218] Purpose: To prepare, test and evaluate multiple formulations of
Sodium Oxybate and two formulations using alternative salts of
gamma-hydroxybutyrate.

[0219] Scope: Various formulations of Sodium Oxybate in water were
prepared with addition of selected acidulents at multiple Ph levels.
Solutions were prepared and tested at Neo-Pharm Laboratories, Blainville,
Quebec. All formulations successfully prepared were placed on limited
stability. Earlier studies have demonstrated that degradation products
are formed in acidic conditions and that antimicrobial effectiveness is
limited at high Ph. Conditions of varying Ph and concentrations of sodium
oxybate previously not evaluated were prepared and tested.

[0220] Procedures: Solutions were prepared as summarized and microbial
challenge testing carried out as follows:

[0221] B. Evaluation of Sodium Oxybate Formulations

[0222] Purpose: To prepare, test and evaluate multiple formulations of
Sodium Oxybate and two formulations using alternative salts of
gamma-hydroxybutyrate.

[0223] Scope: Various formulations of Sodium Oxybate in water were
prepared with addition of selected acidulents at multiple Ph levels.
Selected formulations were studied for limited stability. Earlier studies
demonstrated that degradation products are formed in acidic conditions
and that antimicrobial effectiveness is limited at high Ph. Conditions of
varying Ph and concentrations of sodium oxybate previously not evaluated
were prepared and tested.

[0224] Responsibility: It was the responsibility of Neo-Pharm Laboratories
to prepare selected formulations and perform testing per this protocol.
Orphan Medical, New Medicine Development and Quality Assurance were
responsible for reviewing raw data at the defined decision point,
defining which formulations will be included in stability testing. Orphan
Medical was also responsible for reviewing final results (raw data) and
the final report.

[0225] Procedure: The following formulations were prepared by scientists
at Neo-Pharm following the steps listed below and dispensed into
containers (amber PET 240 ml bottle, OMI CS-460) and closures (Clic-Loc
III, 24-400, OMI CS-470) to a volume of 200 ml each bottle. The bottles
were tested by 28-day microbial challenge and by limited stability
testing at 25° C. including appearance, Ph, potency, and impurity
profile on day 1 (day of preparation) and day 28.

[0227] 1. Preparation: Method for Preparation of Various Formulations:
As previously determined in PR98068, the method of choice for preparation
of liquid formulations of sodium oxybate was the following: [0228] a.
For a one liter quantity of product, add the sodium oxybate in 500 ml of
purified and stir until dissolved. Prepare a 10% solution of the acid
(Malic or Citric) and add slowly to the solution of sodium oxybate. The
solution should be monitored for Ph and temperature and both variables
recorded at reasonable intervals (every 10 or 15 minutes). When the
target Ph is attained, the solution will be Q. S. to 1 liter and Ph
rechecked and recorded. [0229] b. The final solutions will be filtered
through 10 μm filters and 200 Ml dispensed into 5 amber PET bottles
with closures (quadraturerovide by Orphan Medical, Inc.). Two bottles
will be used for microbial challenge studies and the remaining three
bottles will be placed on limited stability. [0230] 2. Testing:
Formulations were tested by two methods of evaluation: [0231] a. Limited
stability evaluation: [0232] (1) Storage Conditions: 25° C.
[0233] (2) Pull Points: Day 0 (day of preparation), and day 28 [0234] (3)
Testing Requirements:

[0245] 1. Solubility determination: Little information is available
about the solubility of this alternative salt of gamma-hydroxybutyrate
and a determination of solubility was done in advance of efforts to
prepare formulations for evaluation by stability and microbial challenge.
Maximum solubility is evaluated for pH unadjusted solutions and within
the pH range desired for this formulation (pH 6.0-8.0). If solubility is
limited, the formulation will be changed to accommodate the solubility
limitations. The preferred acidulent for this work is Malic acid. If acid
is not compatible with the salt, then an alternative acid can be
selected. [0246] 2. Preparation: Method for preparation of alternative
salt formulations: [0247] a. The previously described method (Part A) is
used for preparation of formulations of calcium gamma-hydroxybutyrate at
the concentrations and specified pH determined by solubility experiments.
[0248] b. The final solutions were filtered through 10 μm filters and
dispensed into 5 amber PET bottles with closures (provided by Orphan
Medical, Inc.). Two bottles are used for microbial challenge studies and
two bottles are placed on limited stability. The remaining bottles are
retained for any additional studies at a future time. [0249] 3. Testing:
Formulations are tested as described above.

[0250] C. Reporting of Results: The results will be reported for the
Stability and Microbial Challenge results in standard format as defined
by the described Orphan Medical Development. Copies of HPLC chromatograms
and any raw data from these studies will be provided with results.

[0251] D. Acceptance Criteria: Specific acceptance criteria for this study
can be described analogous to those for sodium oxybate.

[0252] Results: Summarized as follows in Tables 18, 19 and 20 for various
studies.

[0254] This report summarizes the results of the above described study and
provides a summary of previous development work which evaluated
conditions other than those evaluated in this study. The purposes of this
information is to define the scope and limitations of the self-preserving
properties of Xyrem® oral solution for completion of patent
application.

II. Summary of Results:

[0255] A. Preparation of Various Formulations of Sodium Oxybate and
Formulations Using an Alternative Salt of GHB. [0256] 1. Various
formulations of sodium oxybate were prepared as directed in the above
Protocol. Sodium oxybate. 500 mg/cc with Malic Acid was not soluble at pH
5.0, and further evaluation of this solution was discontinued. All other
solutions were successfully prepared as described. [0257] 2. The
preparation of an alternative salt of gamma-hydroxybutyrare was described
as the calcium salt, prepared at 500 mglcc (or maximum possible) with
Malic Acid at pH 7.5. [0258] a. The calcium salt of
gamma-hydroxybutyrate was prepared by Toronto Research and shipped to
NeoPharm for determination of solubility and evaluation according to the
Protocol. The absolute limit of solubility, without pH adjustment, was
determined to be 700 mg/cc. The pH of this solution was 8.4. Solutions of
lower pH were more difficult to prepare at 500 mg/cc using Malic acid, as
acidulant. When pH was adjusted to 6.0 with Malic acid. the solubility of
the calcium oxybate was limited (longer stifling required to solubilize).
The desired solution of 500 mg/cc, pH 7.5 was prepared with Malic acid as
acidulant without difficulty. Appearance of the final solution was
slightly yellow in color. Copies of the laboratory record for preparation
of these solutions is available.

[0259] B. Microbial Challenge Testing of the Various Formulations Prepared
by MDS NeoPharm.

[0260] The microbial challenge testing was carried as specified in the
Protocol and the following table summarizes the results of microbial
challenge testing of various formulations of sodium oxybate and the
single calcium oxybate formulation prepared.

[0264] All of the compositions and/or methods disclosed and claimed herein
can be made and executed without undue experimentation in light of the
present disclosure. While the compositions and methods of this invention
have been described in terms of preferred embodiments, it will be
apparent to those of skill in the art that variations may be applied to
the compositions and/or methods and in the steps or in the sequence of
steps of the method described herein without departing from the concept,
spirit and scope of the invention. More specifically, it will be apparent
that certain agents which are both chemically and physiologically related
may be substituted for the agents described herein while the same or
similar results would be achieved. All such similar substitutes and
modifications apparent to those skilled in the art are deemed to be
within the spirit, scope and concept of the invention as defined by the
appended claims.